The working hypothesis of this Program Project is that aging comprises a gradual progression of declines in tissue function caused by changes in basic intrinsic processes, and that these often alter the structure and function of key regulatory molecules for genes whose products are vital to protect against stress-mediated tissue damage and proliferative activation. Our long-term goal is to determine whether aging affects the structure and function of regulatory factors that control gene expression and proliferation. The Specific Aims of the initial project period are to determine whether (a) the activity of key regulatory or trans-acting factors for genes that respond to inflammation, injury, or stress are altered by aging; and (b) whether functional failure of cells and tissues in aging is due to attenuated activity of these regulatory molecules. The scientific five components of this Program Project will address these two broad aims using a variety of approaches to examine the effects of aging on intrinsic processes in several rodent tissues. Project 1 (JP) will focus on age-related changes in regulation of the acute phase response to bacterial lipopolysaccharide (LPS) in the mouse liver, while Project 4 (EAT) will examine age-associated changes in transcriptional regulation of genes encoding ribosomal components of LPS-stimulated B lymphocytes. Both the acute phase and proliferative responses are markedly reduced in aged rodents. Project 3 (RP-P) and Project 2 (JL) will focus on age-associated deterioration in the central nervous system: Project (3) will concentrate on reduced efficiency of nerve growth factor and its receptors, and the interactions of this growth factor with corticosteroids in the hippocampus and basal forebrain; Project 5 (PW) will examine mechanisms responsible for altered serum/lymph hyaluronate levels with aging and their possible role as a basis for reduced proliferative response in B lymphocytes and neuronal cells. Additionally, Administrative and Molecular Biology Cores will provide administrative oversight and molecular biological facilities and expertise to the five scientific projects. These five projects complement one another both mechanistically and theoretically. Programmatic interactions will include: sharing tissues among the various investigators to reduce animal costs; consulting with one another both as to experimental design, methodological approaches, and data analysis; and active collaborations. By bringing a range of different approaches to bear on various age-related changes in stress responses in different experimental systems, we will more clearly discern common regulatory themes that effect the decline in proper tissue functions with age.